The invention relates in general to hydrogel compositions. More particularly, the present invention relates to ionically crosslinked hydrogels and a method for preparing and adjustably controlling the rate of gelation of the same.
Hydrogels are insoluble, hydrophilic water-containing gels, which are made from water-soluble polymers. See, for example, J. I. Kroschwitz, Concise encyclopedia of polymer science and engineering, New York: Wiley. xxix, 1341 (1990); and H. F. Mark and J. I. Kroschwitz, Encyclopedia of polymer science and engineering, 2nd ed. New York: Wiley. v. (1985). Hydrogels have received significant attention in the past three decades because of their high promise in biomedical applications. See, for example, N. A. Peppas, Hydrogels in medicine and pharmacy, Boca Raton, Fla.: CRC Press. (1986); and B. D. Ratner, Biomaterials science: an introduction to materials in medicine, San Diego: Academic Press. xi, 484 (1996). Their biocompatibility makes them widely used in the food industry, clinical medicine, pharmaceutical industry, and biomedical research. Food additives, contact lenses, blood contact materials, controlled release formulations, wound dressings, bioadhesives, membranes, superabsorbents, cell encapsulation and immunoisolation materials, and tissue engineering scaffolds are some of the examples. See, for example, P. Aebischer, E. Buchser, J. Joseph, J. Favre, N. de Tribolet, M. Lysaght, S. Rudnick, and M. Goddard, xe2x80x9cTransplantation in humans of encapsulated xenogeneic cells without immunosuppression: A preliminary reportxe2x80x9d. Transplantation, 58(11): 1275-1277 (1994); L. J. Suggs, E. Y. Kao, L. L. Palombo, R. S. Krishnan, M. S. Widmer, and A. G. Mikos, xe2x80x9cPreparation and characterization of poly(propylene fumarate-co-ethylene glycol) hydrogelsxe2x80x9d. J Biomater Sci Polym Ed, 9(7): 653-666 (1998); and A. Atala, L. Cima, W. Kim, K. Paige, J. Vacanti, A. Retik, and C. Vacanti, xe2x80x9cInjectable alginate seeded with chondrocytes as a potential treatment for vesicoureteral reflux.xe2x80x9d J Urol, 150(2 Pt 2): 745-747 (1993).
In one prior attempt at making and using hydrogels, sodium alginate was dissolved in water. If cells, proteins or the like were to be included, they were then mixed into the alginate/water solution. The alginate solution was then dripped (via a syringe or the like) into a CaCl2 solution. The outer surface of the alginate solution drop would immediately react with calcium ions to form a bead having a crosslinked outer surface. There are several drawbacks inherent in this procedure. First, the rendered structure is limited to beads having no uniformity, ie. there is no internal structurexe2x80x94the beads simply have a liquid interior with a hardened, crosslinked outer surface. This would lead to structurally non-homogeneous and mechanically weak alginate gels with undefined dimensions. Second, the rate of gelation is extremely fast and uncontrollable, which is undesirable in applications requiring slower and/or controllable gelation rates.
In other prior attempts at making and using hydrogels, harmful chemical crosslinking reagents were used. However, these reagents are toxic to cells and/or biosystems, and cannot be used for or with such cells and/or biosystems.
In yet another attempt at making and using hydrogels, alginate gels were proposed for use as impression material in dentistry. In this method, because alginates in and of themselves are so weak, about 50% ceramic powder is mixed with the alginate. Phosphate is then added as a retarder to the alginate/ceramic powder mixture in order to slow down the very fast reaction of the calcium ions with the alginate. The calcium ions from dissolved CaCl2 react first with the phosphate, then the remaining calcium ions react with the alginate. However, drawbacks also exist in this method. Cells and the like cannot be incorporated into a gel including ceramic powderxe2x80x94cells and the like need a pure, clear gel in order to live and grow. Further, the use of phosphate as a reaction retarder greatly weakens the strength of the gel.
As can readily be appreciated, the need exists for, and it is an object of the present invention to provide structurally homogeneous and mechanically strong hydrogels having defined dimensions. It is another object of the present invention to provide such hydrogels wherein the rate of gelation is selectively variable and controllable.
The present invention addresses and solves the above-mentioned problems and meets the enumerated objects and advantages, as well as others not enumerated, by providing a biocompatible hydrogel composition, consisting essentially of:
at least one water-soluble polymer formed by polymerization of one or more monomers, the polymer being present in a predetermined concentration;
at least one of: a slow dissolving divalent or multivalent cation-containing compound; a slow releasing divalent or multivalent cation-releasing compound; a fast dissolving divalent or multivalent cation-containing compound; and a fast releasing divalent or multivalent cation-releasing compound, the at least one cation containing/releasing compound being present in a predetermined concentration;
wherein at least one of the monomers is selected from the group consisting of acids, monomers containing an acid group, monomers containing a derivative of an acid, and mixtures thereof, wherein the at least one monomer reacts with the divalent or multivalent cations to form ionic crosslinks intermolecularly among polymer chains to form an ionically crosslinked hydrogel composition at a gelation rate;
and wherein at least one of the concentration of the cation-containing/releasing compound and the concentration of the polymer substantially controls the gelation rate.
A method for preparing such an ionically crosslinked hydrogel composition comprises the step of controlling a rate of gel formation of the hydrogel composition by varying at least one of solubility of the cation containing compounds, cation concentration, mixture/ratio of cation containing compounds, polymer concentration, and gelation temperature.